Correlation of Vulnerable Coronary Plaques to Sudden Cardiac Events. Lessons from a Myocardial Infarction-prone Animal Model (the WHHLMI Rabbit)

Abstract

It is generally considered that coronary rupture-prone plaques play an important role in the onset of sudden cardiac events (acute coronary syndromes/sudden cardiac death). However, it is not clear which factors or stimuli are required to trigger plaque rupture and whether coronary plaques without occlusive thrombi can cause sudden cardiac events. To address these issues, recently, we developed a rabbit model of spontaneous myocardial infarction [ the Watanabe heritable hyperlipidemic (WHHL) MI rabbit ] and found that this model possessed several types of coronary plaques that are possibly correlated to sudden cardiac events. Although many of the coronary plaques of the WHHLMI rabbits appeared histologically to be rupture-prone in nature, true rupture was detected only in the few animals that died of MI. In addition, no occlusive thrombus was detected in any WHHLMI rabbit. These findings suggest that some additional stimuli play a definitive role in causing disruption of rupture-prone plaques and thrombosis. Nearly-occluded plaques caused by a luminal macrophage accumulation are the most common feature of WHHLMI rabbits, suggesting that they are responsible for sudden cardiac events. The WHHLMI rabbit could be a useful model for studying the mechanism(s) of plaque rupture and thrombogenesis if plaque rupture/thrombus formation is induced in the rupture-prone plaques of WHHLMI rabbits by administration of additional triggering factors, and could provide a novel means for developing new therapies.

Distribution Profiles of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP), Matrix Metalloproteinase-2 (MMP-2) and Cyclooxygenase-2 (COX-2) in Rabbit Atherosclerosis: Comparison with Plaque Instability Analysis

“…15,20) Our findings, namely relatively strong COX-2 staining with weak staining of MT1-MMP in more stable atherosclerotic lesions, appear to support the dual-phase functions of COX-2 reported by Cipollone et al 12,15,20) Methodological Considerations In the present study, WHHLMI rabbits were used to determine the distribution profiles of MT1-MMP, MMP-2 and COX-2 in comparison with plaque instability analysis, because they have several advantages as an animal model for studying atherosclerosis: (1) lipoprotein profile similar to that of humans, (2) susceptibility to the development of atherosclerosis, (3) lesion characteristics (from early to advanced stage) similar to those in humans. 22,23,35,36) One drawback in our rabbits is that they failed to show any lesion ruptures or thrombosis, although rupture-prone unstable plaques characterized in humans as those consisting of thin fibromuscular caps and large lipid cores with numerous macrophages were observed in the aortic lesions of our rabbits. The atherosclerotic lesions found in the aortas of our rabbits may not exactly follow the process leading to plaque rupture, which may partly explain the discrepancy between the present results and the previous clinical studies.…”

Xist Deficiency and Disorders of X-Inactivation in Rabbit Embryonic Stem Cells Can Be Rescued by Transcription-Factor-Mediated Conversion

“…T he rabbit is a classic model animal that shares anatomical, physiological, genetic, and biochemical features that are more closely related to primates than either the mouse or rat; thus, this species is more suitable for modeling human pulmonary, cardiovascular, neurological, and metabolic disorders [1][2][3][4]. Although the derivation of germline-competent rbESCs or rbiPSCs would be invaluable for generating precise gene-modified rabbits, neither has been successfully established.…”

Naive-like Conversion Overcomes the Limited Differentiation Capacity of Induced Pluripotent Stem Cells

“…It has a short gestation period (31 days) and shows high fecundity. For these reasons, a number of research groups have long used the rabbit in biomedical research, and it has served as a model for human diseases (21,22). Many of these diseases are lifestyle-related, and their prevalence is increasing rapidly in developed countries.…”